You don't usually hear people compare Food and Drug Administration advisory committee meetings to a world-class sporting event, but this is how Brian Denger described the one set for Monday:
"For the Duchenne community, this is going to be more like the Super Bowl," Denger, a supermarket manager from Biddeford, Maine, told me.
The "Duchenne community" refers to people touched by Duchenne muscular dystrophy, or DMD, the most common and most severe form of muscular dystrophy. Denger is a member because he is the father of two sons with DMD.
Worldwide, about 1 in 3,500 boys--DMD almost exclusively affects boys--inherit the genetic disease, which is passed on the X chromosome from mothers to sons. Affected boys begin to exhibit symptoms of muscle weakness between the ages of 3 and 5. By 12, most can no longer walk. Eventually, the disease weakens their heart and the muscles involved in breathing, and they die, typically before their 30th birthday.
No approved drug can slow the course of any type of muscular dystrophy, let alone reverse or cure it, which is why hundreds of members of the Duchenne community--parents, patients, doctors, scientists and other advocates--are expected Monday to pack the Chesapeake Ballroom at the College Park Marriott Hotel and Conference Center in the Washington, D.C., suburb of Hyattsville, Md., a few miles from the FDA's sprawling Silver Spring campus.
Their mission: to convince members of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee that they should recommend approval of Sarepta Therapeutics' New Drug Application, or NDA, for eteplirsen. The agency usually follows its advisory committee recommendations but is not bound by them.
Can the DMD community, which argues that "eteplirsen keeps more boys on their feet," trump FDA scientists' unfavorable assessment of the drug? Should it? While the FDA doesn't consider cost when deciding whether to approve a new drug, the thought that what is bound to be an extremely expensive treatment (Vertex has priced Kalydeco, which treats people with certain mutations in the cystic fibrosis gene, at more than $300,000 a year) might be only minimally effective, if that, is sobering.
"Although FDA is prepared to be flexible with respect to a devastating illness with no treatment options, flexibility does not mean approving drugs for which substantial evidence of effectiveness has not been established," concluded a briefing document posted Thursday by the FDA. Still, the FDA reviewers noted, "it is important to recognize that no final conclusions have been reached on the approvability of this application."
Pat Furlong, founding president and CEO of Parent Project Muscular Dystrophy, an advocacy group based in Hackensack, N.J., says she's optimistic. "I do think that hearing the patients' stories, hearing the patients' experience with this compound...will be persuasive," Furlong, whose two sons died of DMD, told me. "I think the FDA learns a great deal from listening to patients."
Few so-called disease communities are as well-organized and as well-connected as Furlong's. "Take a Stand. Fill a Seat. Raise Your Voice," urges MakeDuchenneHistory.com. "We represent friends, families, and patients affected by Duchenne Muscular Dystrophy who want to see safe, effective treatments approved by the FDA."
They have friends in high places:
- In a letter dated April 15, a bipartisan group of 24 senators urged Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, to use the agency's "broad regulatory flexibility...to help advance new DMD therapies."
- Rick Santorum, former U.S. Senator and former Republican presidential candidate, tweeted Saturday that he plans to attend the advisory committee meeting. Santorum's own daughter was born with a genetic disorder called Trisomy 18.
- Sen. Marco Rubio, R-Fla., another former Republican presidential candidate, tweeted earlier this month that he "met with DMD advocates to chat about how FDA can accelerate approval of innovative therapies."
Scores of DMD advocates, including Denger, are scheduled to address the advisory panel at a public hearing after lunch. Demand was so great that the FDA added a half-hour to the hearing's originally scheduled two hours (already about twice as long as a typical FDA public hearing) and held a lottery to pick the people who'd get the coveted three-minute slots to speak. To squeeze in as many speakers as possible, some advocates who won a slot will split their time with others who didn't.
According to Sarepta, based in Cambridge, Mass., eteplirsen increases levels of a protein called dystrophin. DMD is associated with errors in the gene that codes for dystrophin, one of a group of proteins that strengthen and protect muscle fibers. People with DMD typically don't produce any functional dystrophin.
Eteplirsen is designed to treat boys with the most common type of mutation in the dystrophin gene, who make up about 13% of all DMD patients, according to Sarepta. Annie Kennedy, senior vice president of legislation and public policy for Parent Project Muscular Dystrophy, estimates that about 2,300 U.S. boys with DMD have the type of mutation amenable to treatment with eteplirsen.
Using an approach similar to eteplirsen, Sarepta's website says, the company has also begun early human testing of drugs for the second and third most common types of DMD mutation. Sarepta says it is in the discovery or pre-human testing phase of potential treatments for DMD caused by seven other types of mutations in the dystrophin gene.
"I think what the community understands (is) even if your child is not amenable to this drug, the ramifications for the entire community are huge," said Will Nolan, senior vice president of administration and communications for Parent Project Muscular Dystrophy.
The advisory committee meeting was originally scheduled for Friday, Jan. 22, but the FDA postponed it at the last minute because of "Snowzilla," a major winter storm forecast for that weekend in the Washington area. The delay presented advocates and Sarepta with an unusual opportunity--a long lead time to prepare responses to the FDA scientists' evaluation.
"FDA should be influenced little, if at all, by patient wishes but a lot by the risks of the disease--and it is," Henry Greely, director of Stanford Law School's Center for Law and the Biosciences, told me. For example, he said, "pancreatic cancer drugs can be much less safe and effective than acne medication."
"I'm sure FDA is taking the fact that DMD is untreatable and awful into account," Greely said. "But it still must, by law, and should (emphasis Greely's), by ethics and policy, approve only drugs that are proven sufficiently safe and effective."
Clearly, the FDA has set a higher bar than the advocates, but if any disease community is going to be able to sway the advisory committee and the FDA, it might well be the DMD community.
"In an effort to influence the direction of DMD research, Parent Project Muscular Dystrophy...recently initiated and drafted guidance for the pharmaceutical industry," Dr. Yoram Unguru, a Johns Hopkins bioethicist and pediatric hematologist/oncologist, noted in an article published in 2015.
The DMD guidance was the first FDA guidance drafted by a disease community "and speaks to the degree of influence the DMD advocacy community carries," Unguru wrote. Significantly, he wrote, the very first section of the guidance "discusses families' willingness to accept undetermined and more risky interventions because of the progressive and unpredictable nature of DMD."
Still, FDA regulations governing drug approvals "are there for a very good reason," Unguru, who sees patients at the Children's Hospital at Sinai in Baltimore, told me. "We need to make sure that patients...and their parents are not given false hope. We all have hope, and hope is good, and hope is important." But if it's misguided hope, hope based on a false promise, "we're getting into a difficult situation."
Agency staff who reviewed Sarepta's NDA found that scientific evidence of eteplirsen's safety and effectiveness is lacking.
The single randomized, double-blind, placebo-controlled study in the NDA was conducted with only 12 boys for 24 weeks at a single medical center, the FDA reviewers have noted in briefing documents for the advisory committee. In this type of study, considered the gold standard for evaluating new treatments, the equivalent of a coin toss determines which participants will receive the experimental therapy and which will get a placebo. "Double blind" means that neither the research subjects nor the researchers learn who got which treatment until the treatment period ends.
At the end of 24 weeks, the boys who had been getting eteplirsen couldn't walk farther in six minutes--a standard test--than the boys who'd been getting the placebo, according to the FDA reviewers. At that point, the four boys who'd been receiving the placebo were switched over to eteplirsen, and all 12 boys in the study have continued to receive weekly infusions of the drug.
The FDA reviewers said they might have accepted levels of dystrophin in patients' muscles as evidence that the drug was working, but biopsies after 3 1/2 years of treatment found that the boys' levels were still far below those generally seen in a milder form of muscular dystrophy. On top of that, the FDA scientists said, there was no apparent correlation between how far the treated boys could walk in six minutes and the dystrophin levels in their muscles.
Dr. Michael Carome, a kidney specialist who directs the Public Citizen Health Research Group, a consumer watchdog organization in Washington, D.C., is blunt about what the FDA should do.
"Based upon the evidence presented and reviewed by the FDA and described in the briefing packet, the drug should not be approved," Carome, who previously worked for the Office for Human Research Protections in the
"It would be a mistake for the FDA to approve this," he continued. "It would be giving in to political pressure and essentially eviscerating their standard for approval. What these patients need is a drug that works... To put out a drug that's not effective isn't helping anyone."
But the FDA scientists have it wrong, according to a lengthy letter sent Feb. 24 to Dr. Billy Dunn, director of the division of neurology products at the FDA. M. Carrie Miceli and Dr. Stanley Nelson, co-directors of the Center for Duchenne Muscular Dystrophy at UCLA, wrote the letter, which was also signed by 34 other U.S. and Australian basic scientists and physicians with expertise in the disease.
“It is remarkable that a viable treatment option may soon be available to add to our clinical approach to this devastating disease,” they wrote.
One thing they did not mention in the letter is that they are married to each other and have a 15-year-old son named Dylan Miceli-Nelson who has Duchenne, although he is not a candidate for eteplirsen. The 8th grader is a “sit-down comedian” whose YouTube video has garnered more than 330,000 views.
I talked recently with Miceli and Nelson, who told me they have no ties to Sarepta, financial or otherwise.
"People advocate for their patients, without a doubt," Miceli said. "But I think the data have really gotten sufficiently robust, even though it is only a small number of boys."
The boys who've been on eteplirsen for nearly five years are more likely to still be walking than other boys with DMD who are the same age but have not been treated with the drug, Nelson said. “Our perspective as scientists in this area is we don’t need to come up with complete cures to make a meaningful impact.”
As Pauline McCormack, a senior research associate at Newcastle University's Policy, Ethics and Life Sciences Research Center in England told me, "Something that might seem insignificant in another disease, such as retaining movement in a few muscles, can be more meaningful in Duchenne." McCormack added, "I think the patient voice is vital and has a role alongside clinical expertise and the scientific evidence."
Brian Denger would agree. His older son, Matthew, died in February 2013, six weeks shy of his 21st birthday. He was halfway through his second year of college. "He actually went to school the morning of his death," his father said.
Denger's younger son, Patrick, 21, is in his third year of college, majoring in psychology. Even without any treatment, Patrick's DMD hasn't progressed as rapidly as his brother's did, their father said. Matthew stopped walking at age 8, Patrick not until age 13.
Patrick barely missed qualifying for an eteplirsen trial in Boston in which older patients who can no longer walk are receiving the drug, Denger said.
Although Patrick can still drive a specially equipped car, he can't touch his face with his hands, which made him ineligible for the eteplirsen study in older patients, his father said. "We were both very disappointed."
They've settled for what they view as the next best thing: a trial of drisapersen, a different drug with a similar mechanism of action as eteplirsen. Every Tuesday for the past 15 weeks (except one, when winter weather in Maine grounded them), Denger and his son have caught a 5:30 a.m. flight to Baltimore, where Patrick receives an infusion of drisapersen at the Kennedy Krieger Institute. They then take Amtrak to Washington and get on the Metro to Reagan National Airport for a direct flight home.
Patrick received his first infusion of drisapersen right around the same time the FDA notified BioMarin, based in San Rafael, Calif., that its NDA for the drug was not approvable in its current form.
Denger considers himself to be a practical man, one not susceptible to false hopes. "We realize that this is the first generation for both of these drugs," he said of himself and Patrick. "We also realize that neither one of these drugs represents a cure."